dothiepin-hydrochloride and sibutramine

In order to clarify the mechanism underlying the anti-obesity effects of sibutramine, we examined the effects of sibutramine on extracellular levels of dopamine and 5-hydroxytryptamine (5-HT) through microdialysis in the striatum in unanesthetized and freely moving rats. Sibutramine (5 mg/kg, oral administration (p.o.)) increased extracellular dopamine and 5-HT levels in rat striatum. The tricyclic antidepressant dosulepin (80 mg/kg, p.o. or 1 microM perfusion through the striatal probe) increased 5-HT levels only. Sibutramine-induced dopamine release was antagonized by perfusion of tetrodotoxin (1 microM) through the microdialysis probe in the striatum. However, sibutramine-induced dopamine release was not inhibited by prazosin (1 mg/kg, intraperitoneal injection (i.p.)), a suppressor of serotonergic activity in the striatum via blockade of alpha(1)-adrenoceptors, or perfusion with nomifensine (1 microM), an inhibitor of dopamine re-uptake. These results suggest that sibutramine increases dopamine levels in the striatum by exocytotic release and not by a carrier-mediated mechanism.

Topics: Animals; Corpus Striatum; Cyclobutanes; Dopamine; Dothiepin; Exocytosis; Injections, Intraventricular; Male; Microdialysis; Perfusion; Prazosin; Rats; Rats, Wistar; Serotonin; Tetrodotoxin

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. Alpha-adrenoceptors play an important role in pain processing and alpha2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether alpha-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following alpha1- or alpha2-adrenoceptor antagonism. The antidepressants or monoamine reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin-noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (-)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective alpha1- and alpha2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg(-1); s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (-)-oxaprotiline were all blocked by RX821002 but not by prazosin. Additionally, both morphine and aspirin antinociception was resistant to alpha1- and alpha2-adrenoceptor antagonism. Thus, alpha2- rather than alpha1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Topics: Adrenergic alpha-Agonists; Adrenergic Uptake Inhibitors; Amitriptyline; Analgesics; Animals; Antidepressive Agents; Cyclobutanes; Dothiepin; Drug Interactions; Male; Maprotiline; Mice; Norepinephrine; Pain Measurement; Paroxetine; Random Allocation; Receptors, Adrenergic; Selective Serotonin Reuptake Inhibitors

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Topics: Abdominal Muscles; Acetic Acid; Amitriptyline; Analgesics; Animals; Antidepressive Agents; Cyclobutanes; Dothiepin; Male; Maprotiline; Mice; Muscle Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Neprilysin; Neurotransmitter Uptake Inhibitors; Opioid Peptides; Pain Measurement; Paroxetine; Protease Inhibitors; Receptors, Opioid; Selective Serotonin Reuptake Inhibitors; Thiorphan